Rational design and synthesis of chemical compounds is fundamentally important for the successful development of potent and selective drug leads for a therapeutic target protein. The goal of this Organic Synthesis Core is to provide sustained support of specialized technical expertise in design and synthesis of chemical compounds for the structure-based drug design paradigm proposed in this PPG. The highly coordinated activities of this Core facility will enable the extensive collaborations that are being established for the studies of all three Projects in the PPG, ranging from NMR screening of chemical compounds, structure- activity relationship (SAR) studies of initial binding compounds (IBCs) and lead compounds (LCs) with NMR structural and biochemical analysis, computational modeling, to cellular functional testing of these chemical ligands. The specific aims of this shared Core facility are to prepare chemical analogs of IBCs for SAR studies and to construct and optimize lead compounds. These chemical analogs of IBCs and LCs we will produce with systematic variations of size, position and type of functional groups will significantly enhance our ability to understand modes of interactions between these compounds and the PCAF bromodomain (BRD). Results from the SAR studies with the compounds produced in this Core will feedback into further refinement of these chemical compounds to optimize their structural and chemical features so as to produce chemical inhibitors with high affinity and high selectivity that can effectively block the HIV Tat/PCAF BRD interaction. These iterative and highly coordinated interactions between the Synthesis Core and the other proposed studies of the PPG make it an important component in this PPG that is essential for the development of potent chemical inhibitors for HIV transcription and replication.